PROJECT SUMMARY/ ABSTRACT The overall goal of this proposal is to test the effect of pravastatin, a hepatoselective HMGCoA reductase inhibitor, to delay or avert hepatocellular carcinoma (HCC) recurrence, and gain information regarding the potential mechanical and molecular mechanism of HCC tumor inhibition by pravastatin. HCC is a highly lethal cancer with rising incidence and mortality rates. Fortunately, liver transplantation (LT) offers patients with liver cirrhosis and HCC meeting certain tumor criteria a new lease on life. The downside is the increasing competition for donated livers requires that patients be waitlisted for months or years, increasing the likelihood for HCC progression, loss of transplant candidacy, and death. Cirrhotic patients with HCC are often treated with locoregional therapies (LRT) to `bridge' to LT, however HCC recurrence following LRT is 70-80%. Clinical trials evaluating the effectiveness of adjuvant therapies to delay time to HCC recurrence, allowing patients to remain competitive for curative therapy through LT, is widely considered an area of highly unmet need. There is a growing body of evidence to suggest anti-tumorigenic properties of statins in the liver, and thus they are strong candidates for adjuvant therapy for patients with early stage HCC undergoing LRT. In the proposed study, we will conduct a randomized double-blinded, placebo-controlled Phase IIB trial to test a 12-month intervention with pravastatin versus placebo on time to HCC recurrence. We hypothesize that pravastatin will reduce time to recurrence. Secondarily, we will also test the effect of pravastatin versus placebo on waitlist drop-off, change in the mechanical properties of the liver (liver stiffness), and change in serum biomarkers associated with tumor development and growth. We will enroll 180 study participants over three years from the large pool of patients awaiting LT at three transplant centers in Los Angeles and Chicago. We will focus on patients with transplant- eligible HCC who have completed an initial LRT with complete response. The investigative team is comprised of talented physicians and scientists with complementary expertise including epidemiology, liver transplant surgery, transplant hepatology, medical oncology, and radiation oncology. We are proposing this clinical trial in a well- defined clinical cohort of patients who are under frequent surveillance to remain eligible for a liver transplant. We will harmonize patient recruitment, collection of biological specimens, and follow-up with routine clinical appointments and tests. The proposed study will provide much needed human experimental data on the therapeutic potential of statins for people with HCC. The mechanisms of action for statins in liver carcinogenesis are not well-understood due largely to lack of available human specimens with detailed clinical and statin exposure data. In this trial, we will collect and store serial blood specimens and liver explant tissue from participants on statin and placebo for mechanistic investigations. The confirmation that statins protect against HCC recurrence will provide enormous scientific and public health impact.